Drug Metabolism Letters

Zhiyang Zhao
Cambridge, MA


In Vitro Metabolism Studies of New Adenosine A Receptor Antagonists

Author(s): Gabriella Marucci, Sara Finaurini, Michela Buccioni, Carmen Lammi, Meenakshisundaram Kandhavelu, Rosaria Volpini, Massimo Ricciutelli, Piero Angeli, Jan N.M. Commandeur, Gloria Cristalli.


Evidence, obtained in rodent and primate models of Parkinsons disease (PD) and in preliminary clinical trials, indicates that adenosine A receptor antagonists might represent a promising non-dopaminergic therapeutic tool for the treatment of PD. Recently, we have reported the biological evaluation of 8-substituted 9-ethyladenines (ANR) as new A receptor antagonists, three of which (ANR 82, ANR 94, and ANR 152) showed high efficacy in in vivo models for Parkinsons. Understanding the metabolic pathways of new drug candidates is an important aspect of drug discovery. The ANR compounds have been investigated in order to clarify their activity on rat liver microsomes, and more specifically on recombinant human cytochrome P450 2D6 (CYP2D6). The metabolites of all three compounds were detected by liquid chromatography/tandem mass spectrometry (LC-MS/MS). The results indicate that this class of 9-ethyladenines is metabolized only to a fraction of 1.5-5%. These compounds also act as potent mechanism-based inhibitors of CYP450 and in particular of human isoform CYP2D6. Kinetic-analysis of enzyme inactivation was used to describe the effect of these time-dependent inhibitors and to derive the inhibition parameters K and K defined with respect to the O-demethylation of dextromethorphan.

Keywords: A2A antagonist, A2A adenosine receptors, rat microsome hepatocytes, CYP2D6, 8-substituted 9-ethyladenine, Parkinson's disease, HPLC

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Article Details

Year: 2008
Page: [301 - 307]
Pages: 7
DOI: 10.2174/187231208786734076
Price: $58